Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or CNS). Metastasis is correlated with depth of dermal invasion. With spread, prognosis is poor. Diagnosis is by biopsy. Wide surgical excision is the rule for operable tumors. Metastatic disease requires systemic therapy but is difficult to cure.
(See also Overview of Skin Cancer.)
In 2016, about 76,380 new cases of melanoma occurred in the US, causing about 10,130 deaths. Lifetime risk is about 1 to 2%. Incidence has remained steady over the last 8 yr (it had previously been increasing at a faster rate than any other malignant tumor). Melanoma accounts for < 5% of total skin cancers diagnosed in the US but causes most skin cancer deaths. On average, one person in the US dies of melanoma every hour.
Melanomas occur mainly on the skin but also on the mucosa of the oral, genital, and rectal regions and conjunctiva. Melanomas may also develop in the choroid layer of the eye, in the leptomeninges (pia or arachnoid mater), and in the nail beds. Melanomas vary in size, shape, and color (usually pigmented) and in their propensity to invade and metastasize. Metastasis occurs via lymphatics and blood vessels. Local metastasis results in the formation of nearby satellite papules or nodules that may or may not be pigmented. Metastasis to skin or internal organs may occur, and, occasionally, metastatic nodules or enlarged lymph nodes are discovered before the primary lesion is identified.
Risk factors for melanoma include
Sun exposure, particularly repeated blistering sunburns
Repeated tanning with ultraviolet A (UVA) or psoralen plus UVA (PUVA) treatments
Nonmelanoma skin cancer
Family and personal history
Fair skin, freckling
Atypical moles, particularly > 5
Increased numbers of melanocytic nevi (particularly > 20, depending on family history)
Occurrence of lentigo maligna
Congenital melanocytic nevus > 20 cm (giant congenital nevi)
Atypical mole syndrome (dysplastic nevus syndrome)
Familial atypical mole–melanoma syndrome
Patients with a personal history of melanoma have an increased risk of additional melanomas. People who have one or more 1st-degree relatives with a history of melanoma have an increased risk (up to 6 or 8 times) over those without a family history.
Atypical mole syndrome is the presence of > 50 moles, at least one of which is atypical and at least one of which is > 8 mm in diameter.
Familial atypical mole–melanoma syndrome is the presence of multiple atypical moles and melanoma in ≥ 2 1st-degree relatives; such people are at markedly increased risk (25 times) of melanoma.
Melanoma is less common among people with darker pigmentation; when it occurs, the nail beds, palms, and soles are more often affected.
About 30% of melanomas develop from pigmented moles (about half each from typical and atypical moles); almost all the rest arise from melanocytes in normal skin. Atypical moles (dysplastic nevi) may be precursors to melanoma. The very rare melanomas of childhood almost always arise in the leptomeninges or from giant congenital nevi present at birth. Although melanomas occur during pregnancy, pregnancy does not increase the likelihood that a mole will become a melanoma; moles frequently change in size and darken uniformly during pregnancy. However, the following signs of malignant transformation should be carefully sought:
Change in size
Change in shape, including irregular or indistinct borders
Irregular change in color, especially spread of red, white, and blue pigmentation to surrounding normal skin
Change in surface characteristics or consistency
Signs of inflammation in surrounding skin, with possible bleeding, ulceration, itching, or tenderness
Recent enlargement, darkening, ulceration, or bleeding usually indicates that the melanoma has invaded the skin deeply. Patients at risk can be taught self-examination to detect changes in existing moles and to recognize features suggesting melanoma (see Diagnosis).
There are 4 main types of melanoma and a few minor subtypes.
This type accounts for 70% of melanomas. Typically asymptomatic, it occurs most commonly on women’s legs and men’s torsos. The lesion is usually a plaque with irregular, raised, indurated, and tan or brown areas, which often have red, white, black, and blue spots or small, sometimes protuberant blue-black nodules. Small notchlike indentations of the margins may be noted, along with enlargement or color change. Histologically, atypical melanocytes characteristically invade the dermis and epidermis. This type of melanoma most commonly has activating mutations in the BRAF gene at V600.
This type accounts for 15 to 30% of melanomas. It may occur anywhere on the body as a dark, protuberant papule or a plaque that varies from pearl to gray to black. Occasionally, a lesion contains little if any pigment or may look like a vascular tumor. Unless it ulcerates, nodular melanoma is asymptomatic, but patients usually seek advice because the lesion enlarges rapidly.
This type accounts for 5% of melanomas. It tends to arise in older patients. It arises from lentigo maligna (Hutchinson freckle or malignant melanoma in situ—a frecklelike tan or brown macule). It usually occurs on the face or other areas of chronic sun exposure as an asymptomatic, flat, tan or brown, irregularly shaped macule or patch with darker brown or black spots scattered irregularly on its surface. In lentigo maligna, both normal and malignant melanocytes are confined to the epidermis. When malignant melanocytes invade the dermis, the lesion is called lentigo maligna melanoma, and the cancer may metastasize. This type of melanoma most commonly has mutations in the C-kit gene.
This type accounts for only 2 to 10% of melanomas. Incidence is probably the same regardless of skin pigmentation, but because people with darkly pigmented skin infrequently develop other forms of melanoma, acral-lentiginous melanoma is the most common type among them. It arises on palmar, plantar, and subungual skin and has a characteristic histologic picture similar to that of lentigo maligna melanoma. This type of melanoma often has mutations in the C-kit gene.
Amelanotic melanoma is a type of melanoma that does not produce pigment. It can be any of the 4 main types and is most often grouped with the minor categories of melanoma such as spitzoid melanoma, desmoplastic melanoma, neurotropic melanoma, and others.
Occurring in < 10% of melanomas, amelanotic melanomas may be pink, red, or slightly light-brown and may have well-defined borders. Their appearance may suggest benign lesions, or a form of nonmelanoma skin cancer, and thereby lead to a late diagnosis and possibly a worse prognosis.
Differential diagnosis includes basal cell carcinomas and squamous cell carcinomas, seborrheic keratoses, atypical moles, blue nevi, dermatofibromas, moles, hematomas (especially on the hands or feet), venous lakes, pyogenic granulomas, and warts with focal thromboses.
If doubt exists, biopsy should include the full depth of the dermis and extend slightly beyond the edges of the lesion. Biopsy should be excisional for most lesions except those on anatomically sensitive or cosmetically important areas; in these cases, a broad shave biopsy can be done. For broader lesions such as lentigo maligna, representative shave biopsies from several areas can increase the diagnostic yield. By doing step sections, the pathologist can determine the maximal thickness of the melanoma. Definitive radical surgery should not precede histologic diagnosis.
Pigmented lesions with the following features should be excised or biopsied:
However, these features usually indicate that the melanoma has already invaded the skin deeply. Earlier diagnosis of melanoma is possible if biopsy specimens can be obtained from lesions having variegated colors (eg, brown or black with shades of red, gray, or blue), irregular elevations that are visible or palpable, and borders with angular indentations or notches. Polarized light and immersion contact dermoscopy, which is used to examine pigmented lesions, may be useful for distinguishing melanomas from benign lesions. Because earlier diagnosis can be lifesaving and features of melanoma can be variable, even slightly suspect lesions should be biopsied.
Tumors, particularly if metastatic, are sometimes tested genetically for mutations, eg, to suggest treatment with vemurafenib, a BRAF inhibitor, for metastatic melanomas bearing a V600 mutation in the BRAF gene.
The staging of melanoma is based on clinical and pathologic criteria and closely corresponds to the traditional tumor-node-metastasis (TNM) classification system. The staging system classifies melanomas based on local, regional, or distant disease.
Stage strongly correlates with survival. A minimally invasive microstaging technique, the so-called sentinel lymph node biopsy (SLNB), is a major advance in the ability to stage cancers more accurately. Recommended staging studies depend on the Breslow depth (how deeply tumor cells have invaded) and histologic characteristics of the melanoma; dermal mitoses and ulceration indicate higher risk in melanomas that are < 1 mm Breslow depth (see Table: Staging of Melanoma Based on Thickness and Ulceration). Staging studies may include SLNB, laboratory tests (eg, CBC, LDH, liver function tests), chest x-ray, CT, and PET and are done by a coordinated team that includes dermatologists, oncologists, general surgeons, plastic surgeons, and dermatopathologists.
Melanoma may spread rapidly, causing death within months of its recognition, yet the 5-yr cure rate of early, very superficial lesions is very high. Thus, cure depends on early diagnosis and early treatment.
For tumors of cutaneous origin (not CNS and subungual melanomas) that have not metastasized, the survival rate varies depending on the thickness of the tumor at the time of diagnosis. The 5-yr survival rates range from 97% for patients with stage IA melanomas to 53% for patients with stage IIC melanomas; 10-yr survival rates range from 93% for patients with stage IA melanomas to 39% for patients with stage IIC melanomas.
Mucosal melanomas (especially anorectal melanomas), which are more common among nonwhites, have a poor prognosis, although they often seem quite limited when discovered.
Once melanoma has metastasized to the lymph nodes, 5-yr survival ranges from 25 to 70% depending on the degree of ulceration and number of nodes involved. Once melanoma has metastasized to distant sites, 5-yr survival is about 10%.
Staging of Melanoma Based on Thickness and Ulceration
Degree of lymphocytic infiltration, which represents reaction by the patient’s immunologic defense system, may correlate with the level of invasion and prognosis. Chances of cure are maximal when lymphocytic infiltration is limited to the most superficial lesions and decrease with deeper levels of tumor cell invasion, ulceration, and vascular or lymphatic invasion.
A new commercially available test of gene expression (DecisionDxTM-Melanoma) helps determine whether patients who have stage I or II melanomas are at high or low risk of metastases. This test has not yet been added to consensus guidelines; using it to determine whether patients should receive immunotherapy is not recommended at this time.
Treatment of melanoma is primarily by surgical excision (wide local excision). Although the width of margins is debated, most experts agree that a 1-cm lateral tumor-free margin is adequate for lesions < 1 mm thick. In tumors < 1 mm thick, but with ulceration or at least 1 dermal mitoses/mm2, SLNB can be considered. Thicker lesions may deserve larger margins, more radical surgery, and SLNB.
Lentigo maligna melanoma and lentigo maligna are usually treated with wide local excision and, if necessary, skin grafting. Intensive radiation therapy is much less effective. The ideal treatment of melanoma in situ is surgical excision. Sometimes this can be accomplished with staged excisions or Mohs micrographic surgery, in which tissue borders are progressively excised until specimens are tumor-free (as determined by microscopic examination during surgery). If patients decline or are not candidates for surgical therapy (eg, because of comorbidities or involvement of cosmetically important areas), imiquimod and cryotherapy can be considered. Most other treatment methods usually do not penetrate deeply enough into involved follicles, which must be removed.
Spreading or nodular melanomas are usually treated with wide local excision extending down to the fascia. Lymph node dissection may be recommended when nodes are involved. (See also the American Academy of Dermatology Association’s guidelines of care for the management of primary cutaneous melanoma.)
Treatment of metastatic melanoma typically includes
All of these treatments should be considered for all patients who have metastatic melanoma. Final decisions are generally individualized by an oncologist and may depend on availability.
Metastatic disease is generally inoperable, but in certain cases, localized and regional metastases can be excised to help eliminate residual disease.
Immunotherapy with anti-programmed death (PD-1) antibodies (pembrolizumab and nivolumab) lengthens survival. They inhibit the PD-1 receptor that attenuates T-cell effector responses against cancers.
Ipilimumab (a monoclonal antibody to cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) is another form of immunotherapy that can also lengthen survival. It works by preventing anergy of T cells, thus freeing the immune system to attack tumor cells.
Molecular targeted therapy includes use of vemurafenib and dabrafenib, which function by inhibiting BRAF activity, resulting in slowing or stopping of tumor cell proliferation. These drugs have lengthened survival in patients with metastases; adding mitogen-activated protein kinase (MEK) inhibitor enzymes MEK1 and MEK2 (via trametinib) lengthens survival even more.
Cytotoxic chemotherapy has not been shown to improve survival in patients with metastatic disease and is normally reserved for patients who do not have other options.
Adjuvant therapy with recombinant biologic response modifiers (particularly interferon alfa) to suppress clinically inapparent micrometastases may also be used for inoperable metastatic melanoma.
Radiation therapy may be used to palliate brain metastases, but the response is poor.
The following are under study:
Because melanoma seems to be related to ultraviolet (UV) exposure, a number of measures are recommended to limit exposure.
Sun avoidance: Seeking shade, minimizing outdoor activities between 10 am and 4 pm (when sun's rays are strongest), and avoiding sunbathing and the use of tanning beds
Use of protective clothing: Long-sleeved shirts, pants, and broad-brimmed hats
Use of sunscreen: At least sun protection factor (SPF) 30 with broad-spectrum UVA/UVB protection, used as directed (ie, reapplied every 2 h and after swimming or sweating); should not be used to prolong sun exposure
Melanoma accounts for < 5% of total skin cancers diagnosed in the US but causes most skin cancer deaths.
Melanoma can develop in the skin, mucosa, conjunctiva, choroid layer of the eye, leptomeninges, and nail beds.
Although melanoma can develop from a typical or atypical mole, most do not.
Physicians (and patients) should monitor moles for changes in size, shape, borders, color, or surface characteristics and for bleeding, ulceration, itching, and tenderness.
Biopsy even slightly suspect lesions.
Excise melanomas whenever feasible, particularly when melanomas have not metastasized.
Consider immunotherapy (eg, pembrolizumab, nivolumab), targeted therapies (eg, ipilimumab, vemurafenib), radiation therapy, and excision if melanoma is unresectable or metastatic.